Beta3 integrin-mediated ubiquitination controls survival signaling for compensatory hypertrophic growth

Pressure overload (PO) hypertrophy is initially compensatory but often decompensates into heart failure by a poorly understood mechanism. It is important to identify the molecular mechanisms that contribute to compensated growth and survival of cardiomyocytes during PO that are absent during decompensation. Further, developing a method to prolong or reinitiate these beneficial pathways may create a therapeutic strategy to delay or prevent heart failure. Previous studies in the lab showed enhanced ubiquitination (Ub) near intercalated discs of cardiomyocytes, where integrins are important receptors for cell-cell and cell-matrix interactions, during the early growth period of pressure overload (PO) hypertrophy. This work tested the upstream signal for Ub during PO, whether this enhanced Ub contributes to survival signaling in early PO, if loss of this mechanism could lead to failure, and if upregulation of Ub could enhance survival. A beta3 integrin knockout mouse was utilized for in vivo pressure overload by TAC and for the cardiomyocyte culture model with the integrin-activating peptide RGD. It is demonstrated the beta 3 integrin activates Ub during early PO hypertrophy. Prosurvival signaling proceeds by initiation of NFkappaB transcription of the E3 ligase, cIAP1. When this mechanism is not in place during PO, a heart failure phenotype develops with increased cardiomyocyte death and diminished ventricular function. This is the first study to show that beta3 integrin is required for compensatory hypertrophic growth and that the beta3 integrin induces Ub for regulation of survival signaling during hypertrophy. Since this Ub-mediated pathway is necessary for compensatory growth, it was tested if Ub was coordinating with the Akt pathway. As a key survival kinase in the PI3K/mTOR pathway, Akt is necessary for physiological growth. This work shows rapamycin augments Akt activation and Ub of select proteins for degradation in cardiomyocytes to enhance survival signaling. This therapy introduces a new layer of translational control by activating survival transcripts downstream of NFkappaB, while selectively inhibiting mTOR-mediated protein synthesis. Rapamycin causes upregulation of ubiquitin-mediated degradation to activate NFkappaB for cIAP1 expression and elimination of caspase 3 and thus may be a viable therapy to prevent heart failure due to accumulation of apoptotic proteins.